BBA - Reviews on Cancer 1871 (2019) 248–258

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BBA - Reviews on Cancer

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Review Prostate cancer-specific hallmarks of amino acids metabolism: Towards a paradigm of precision medicine T

Vladislav Strmiskaa,b, Petr Michaleka,b, Tomas Eckschlagerc, Marie Stiborovad, Vojtech Adama,b, ⁎ Sona Krizkovaa,b, Zbynek Hegera,b, a Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno, Czech Republic b Central European Institute of Technology, Brno University of Technology, Purkynova 123, CZ-612 00 Brno, Czech Republic c Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, V Uvalu 84, CZ-150 06 Prague, 5, Czech Republic d Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, CZ-128 40 Prague 2, Czech Republic

ARTICLE INFO ABSTRACT

Keywords: So far multiple differences in prostate cancer-specific amino acids metabolism have been discovered. Moreover, Mitochondria attempts to utilize these alterations for prostate cancer diagnosis and treatment have been made. The prostate Personalized medicine cancer metabolism and biosynthesis of amino acids are particularly focused on anaplerosis more than on energy Prostate production. Other crucial requirements on amino acids pool come from the serine, one‑carbon cycle, glycine Serine synthesis pathway and folate metabolism forming major sources of interproducts for synthesis of nucleobases Sarcosine necessary for rapidly proliferating cells. Considering the lack of some amino acids biosynthetic pathways and/or Warburg effect their extraordinary importance for prostate cancer cells, there is a widespread potential for targeted therapeutic applications with no effect on non-malignant cells. This review summarizes the up-to-date knowledge of the importance of amino acids for prostate cancer pathogenesis with a special emphasis on potential applications of metabolic variabilities in the new oncologic paradigm of precision medicine.

1. Introduction aggressive forms of PCa [3]. Therefore, biomarkers able to detect the early stages of PCa are still of utmost interest. It is worth to note that Cancer cells manifest metabolic alterations that distinguish them some of them (alpha methylacyl-CoA racemase, TMPRSS2-ERG fusion, from cells in normal tissues, and make them vulnerable to anticancer caveolin-1, annexin-3, circulating RNAs, small metabolites, such as 8- agents. From the extensive spectrum of such alterations, a number of hydroxy-2′-deoxyguanosine or amino acids) have provided promising differences in metabolism, biosynthesis and content of both proteino- data, and thus their benefit for PCa screening is still extensively in- genic and non-proteinogenic amino acids have been found highly vestigated [3–8]. In case of the positive results, follow-up examination abundant in prostate cancer (PCa). These metabolic alterations support includes transrectal ultrasonography and magnetic resonance imaging the ability of PCa cells to survive the in unfavourable conditions, such that often enable for a guidance of the only test that can fully confirm as hypoxia, oxidative stress and to feed high energetic demands. and classify PCa – biopsy followed by a histopathology examination. Due to a frequent molecular heterogeneity and clinical variability, Moreover, emission/computed tomography and bone scans are utilized PCa can manifest as a benign growth that can be safely watched or as to detect lymph node and bone metastases [2,9]. aggressive malignancy that can prove fatal [1]. Such variability results The primary approach for the treatment of PCa metastases com- in multiple forms of PCa that differ in onset age, aggressiveness, me- prises androgen ablation using gonadotropin-releasing hormone ana- tastatic potential, hormonal responses, and also markedly complicates logues (zoladex, casodex, etc.) or antiandrogens (enzalutamid) [10]. the diagnostic/prognostic and therapeutic accuracy [2]. The first-line Moreover, to prevent skeletal complications, men with bone metastases PCa screening tool combines a digital rectal examination and quanti- are often treat with zoledronate or denosumab [11]. Men who do not tation of serum prostate specific antigen (PSA). This increases the de- respond to hormone therapy often undergo chemo- or immunotherapy. tection rates and awareness of PCa; however, still false-positive/nega- As a standard chemotherapy, docetaxel and cabazitaxel can be used and tive results are common, as well as poor discriminative ability of are often combined with prednisone [12]. The most recent treatment

⁎ Corresponding author. E-mail address: [email protected] (Z. Heger). https://doi.org/10.1016/j.bbcan.2019.01.001 Received 5 November 2018; Received in revised form 9 January 2019; Accepted 9 January 2019 Available online 29 January 2019 0304-419X/ © 2019 Elsevier B.V. All rights reserved. V. Strmiska et al. BBA - Reviews on Cancer 1871 (2019) 248–258

Fig. 1. The importance of Zn in prostate cells. In healthy cells, zinc transporters (ZIPs) enables for extensive Zn accumulation, which results in inhibi- tion of citrate oxidation and respiration. Contrary to that, PCa cells exhibit genetic transformations (fre- quently epigenetic) that silence ZIPs and inhibit ac- cumulation of Zn. As a result, the Krebs cycle become functional and ATP production is increased making the PCa cells bioenergetically efficient.

option utilizes the patient's own immune system to identify and destroy to significantly correlate with proliferation rates across distinct NCI-60 PCa metastatic cells. For this purpose, sipuleucel-T is tailored auto- cancer cell lines. Gly conversion significantly contributes to the bio- logously by patient's dendritic cells extracted by leukapheresis [13]. synthetic requirements of purines, adenosine triphosphate (ATP) and The dendritic cells are subsequently incubated with the recombinant reduced nicotinamide adenine dinucleotide phosphate (NADPH), which protein PA2024 that activates dendritic cells and helps them to mature. are necessary for cancer cells proliferation. Furthermore, Gly metabo- Despite that, it must be noted that virtually no treatments can effi- lism is tightly interconnected with metabolism of serine (Ser) as dis- ciently cure advanced/metastatic PCa, and the discussed approaches cussed below. Alterations in Gly metabolism that result in elevated Gly are particularly effective in prolonging the patient's life and control the pool and altered ratios to other amino acids are therefore considered as symptoms. Hence, the detailed understanding of PCa-specific metabolic plausible predictors of metastatic PCa [38]. alterations might lead to a development of novel diagnostic and ther- apeutic tools required to improve PCa management. 2.1. Gly biosynthesis and metabolism of tetrahydrofolate (THF) One of the most notorious characteristics of PCa cells is a marked decrease in zinc and citrate (Fig. 1). In normal prostatic gland, com- Deregulation of mitochondrial biosynthetic pathway of Gly, to- pared to other soft tissues, 3–10-fold higher amount of zinc is accu- gether with up-regulation of mitochondrial folate enzymes has been mulated within a peripheral zone inevitably causing inhibition of m- observed in numerous cancer cell lines [45]. Intracellular synthesis of aconitase that can catalyze the stereo-specific isomerization of citrate to Gly is compartmentalized between the cytosol and mitochondria, pro- isocitrate. This phenomenon results in accumulation and secretion of viding two separate enzymatic pathways (Fig. 2). It is worth to note that citrate that is vital intermediate in the tricarboxylic acid (TCA) cycle. the rate of proliferation of prostate cells was found to directly correlate The loss of zinc accumulation during PCa progression results in a pro- with up-regulation of mitochondrial part of enzymes involved in Gly nounced oxidation of citrate and stimulation of TCA cycle, thus making metabolism, namely serine hydroxymethyl transferase (SHMT2), me- the cells more energy-efficient. Moreover, the stimulatory effect is thylene-THF dehydrogenase (MTHFD2), and THF-synthetase. magnified by elimination of apoptogenic influence of zinc [14]. Interestingly, in the same experimental setup, the expression of Therefore, unlike other solid tumors, the metabolism and bio- cytosolic enzymes was not altered, highlighting the key role of mi- synthesis of amino acids in PCa is focused particularly on anaplerosis tochondria in cancer cells proliferation [45]. It should be noted that more than on energy production. Another crucial requirement on amino approx. 10% of PCa cases manifest a significant up-regulation of the acid metabolism comes from the serine, one‑carbon cycle, glycine folate metabolism gene signature [20], indicating them as plausible (SOG) synthesis pathway and folate metabolism providing pools of in- biomarkers for PCa classification. From therapeutic point of view, PCa terproducts for synthesis of nucleobases necessary for rapidly pro- cells have been found highly sensitive to folate manipulation. For in- liferating cells [15]. These facts underpin the potential of specific amino stance, Bistulfi and coworkers identified that even mild dietary folate acids deprivation in PCa therapy [16]. At the level of gene expression, depletion arrested PCa progression in TRAMP mice [21]. These entire SOG pathway is up-regulated in up to 9% of PCa cases. Noteworthy, it facts highlight that combinational therapy utilizing antifolates paired to was shown that expression of Myc, its down-stream targets, as well as approved anticancer agents might lead to marked improvement of PCa TMPRSS2-ERG fusion and Gleason score positively correlate with the therapeutic efficiency. In 1996, Sagaster et al. conducted a randomized SOG pathway signature in PCa cells [15]. Several potentially useful prospective clinical trial using combination of maximal androgen deviations in amino acid patterns have been found between malignant blockade (MAB, orchiectomy followed by Flutamide therapy) with vs. non-malignant PCa cell lines and also in urine of PCa patients Methotrexate (MTX) [46]. Despite only non-significant gains in remis- [17–19]. sion rates (42.3% MAB + MTX vs. 29.6% MAB) were achieved, further Hence, the aim of this review is to summarize the up-to-date investigation of combinations of antifolates with approved cytostatic knowledge about the role of amino acids and their metabolical path- drugs possessing distinct mechanisms of actions might result in im- ways in PCa pathogenesis. Moreover, potential applicability of these provement of outcomes of PCa therapy. biochemical processes for PCa diagnosis, classification and therapy is discussed as well. The overview of the importance of amino acids in PCa pathogenesis and possible utilization of their associated pathways for 2.2. Enzymes driving metabolism of Ser/Gly PCa therapy is summarized in Table 1. On the following pages, three- letter abbreviations (together with systematic IUPAC names) for pro- The ectopic expression of enzymes driving Ser and Gly catabolism, teinogenic and well-established abbreviations for non-proteinogenic namely phosphoserine aminotransferase (PSAT) and SHMT is capable amino acids are utilized. to induce prostate tumor formation in vivo [25]. Interestingly, this phenomenon was closely dependent on enhanced activity of glycine decarboxylase (GLDC). Taken together, this phenomenon explains the 2. Glycine (Gly, aminoethanoic acid) fact, that an increased availability of Gly or sarcosine (Sar) results in an enhanced invasiveness of PCa cells [38], and that Gly uptake and cat- Despite its simple structure and high abundance, Gly has been found abolism have marked stimulatory effects on prostate tumorigenesis and

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Table 1 Overview of the roles of amino acids in a pathogenesis of PCa.

Amino acid Importance for PCa cells Possible linkage to PCa therapy Ref.

Glycine (Gly, G) Deregulation of mitochondrial biosynthesis Folate depletion, Antifolates [20,21] Up-regulation of THF metabolism DNA demethylating agents, bases analogs Ser/Gly metabolism Ser/Gly starvation Glutamine (Gln, Q) Production of fatty acids and nucleotides precursors in TCA cycle (α- Carbohydrate and Gln restriction [22,23,24] ketoglutarate) Glutaminolysis Serine (Ser, S) Increased biosynthesis PHGDH targeting [15,25,26] SOG pathway Antifolates Shifting from OXPHOS to glycolysis PKM2 targeting Zinc metabolism Proline (Pro, P) Apoptotic signaling PRODH inhibitors [27,28] ROS scavenging Pyridines precursors Arginine (Arg, R) Up-regulation of Arg metabolism NOS or arginase targeting [29,30] Arg deprivation Leucine (Leu, L) LATs up-regulation Leu analogues for LATs targeting [31,32] Activation of mTOR signaling by Leu Methionine (Met, M) Crucial for protein synthesis, chromatin and protein methylation Met restriction [33,34][35] GSH synthesis Urinary marker of PCa progression Hcy is not used as Met precursor Tryptophan (Trp, W) Serotonin precursor IDO targeting to prevent Trp degradation [36,37] Immunoregulation Sarcosine (Sar) PCa proliferation and invasiveness Sar detection for PCa sub-classification [17,38,39] Intermediate in Gly synthesis Connected with others metabolism of Met, Ser, Gly Hydroxyproline (Hyp) Precursor of Gly, pyruvate and glucose Urinary marker of PCa bone metastases [40,41] ROS scavenger Taurine (Tau) Decreases expression of PSA and metastasis-related proteins Tau and N-acyl Tau treatment decreases cell proliferation and [42,43,44] Attenuates EMT-related genes neoplasticity Putative signaling molecule

THF, tetrahydrofolate; TCA, tricarboxylic acid; PHGDH, phosphoglycerate dehydrogenase; SOG, serine, one‑carbon cycle, glycine; PKM2, pyruvate kinase 2; ROS, reactive oxygen species; PRODH, proline dehydrogenase; NOS, nitric oxide synthase; LATs, L-type amino acid transporters; mTOR, mammalian target of rapamycin; GSH, reduced glutathione; Hcy, homocysteine; IDO, indoleamine 2,3-dioxygenase; EMT, epithelial-mesenchymal transition.

major methyl donor S-adenosylmethionine (SAM), thus regulating in- tracellular methylation processes whose disequilibrium is considered the major hallmark of cancer development and progression [47]. These findings open new avenues for testing the DNA demethylating agents in PCa therapy. Some promising preclinical in vitro and in vivo studies have already been achieved using Disulfiram [48] or Decitabine [49]. In 2007, a phase I/II study revealed that Azacitidine can reverse clinical resistance of metastatic PCa to Docetaxel through epigenetic dereg- ulation [50]. One can speculate about the possible efficiency of Gly deprivation as auxiliary tool during PCa therapy. Indeed, several stu- dies revealed that dietary Gly and Ser starvation can reduce tumor growth in xenograft and allograft models [51–53]. Notably, K-ras- driven cancers were less responsive to Ser/Gly starvation, suggesting an importance of K-ras in regulation of expression of enzymes involved in Fig. 2. Schematic drawing of cytosolic and mitochondrial Gly metabolism. Red Ser/Gly metabolism [54]. – mitochondrial enzymes, blue, cytosolic enzymes. MTHFD2 – Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial, – MTHFD1L Monofunctional C1-tetrahydrofolate synthase, mitochondrial, 3. Glutamine (Gln, 2-amino-4-carbamoylbutanoic acid) SHMT2 – Serine hydroxymethyltransferase 2, SHMT1 – Serine hydro- xymethyltransferase 1, MTHFD1 – C-1-tetrahydrofolate synthase, cytoplasmic, Gln is a non-essential proteinogenic amino acid playing a central THF – tetrahydrofolate, CHO-THF – 10-formyl-tetrahydrofolate, CH2-THF – role in the metabolism of majority of amino acids. Gln comprises up to 5,10-methylenetetrahydrofolate. Adapted and modified according to Jain et al. fi [45]. (For interpretation of the references to color in this figure legend, the 60% of the total free amino acids in blood plasma. Despite its classi - reader is referred to the web version of this article.) cation, Gln shows to be conditionally essential under some physiolo- gical conditions, particularly due to its involvement in several meta- bolic pathways and cell signaling. Moreover, Gln acts as nitrogen donor malignancy [25]. for purine and pyrimidine nucleotide synthesis, synthesis of other Another substantial example of importance of Ser/Gly metabolism amino acids, carbamoylphosphates, amino sugars and other metabolites enzymes was evidenced in our previous study, demonstrating that upon crucial for cellular proliferation. In addition, especially in cancer cells, Gly exposure, expression of Sar metabolism-related enzyme glycine N- Gln serves as carbon donor and an energy source for a broad number of methyltransferase (GNMT) was up-regulated in metastatic PCa cells cellular processes [55]. (PC-3) and primary tumor cells (22Rv1), but not in cells derived from normal prostate epithelium (PNT1A) [17]. During this process, elevated intracellular Sar is formed from Gly by adding a methyl group from a

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3.1. Regulation of Gln metabolism and importance of glutaminolysis Therefore, it is obvious that the regulation of Ser metabolism is of ut- most importance for the tight control of epigenetic processes, particu- In cancers, glutamic acid (Glu) metabolism is tightly regulated by larly DNA methylation [66] that is crucial for controlling the majority several factors, such as MYC, p53, Ras and HIF. This modulation is of cellular functions. maintaining cancer growth, and is one of the important inducers of At the gene expression level, SOG pathway enzymes are up-regu- carcinogenesis [22]. lated in up to 9% of PCa cases. Noteworthy, it was shown that ex- During this process, Gln is converted to glutamic acid (Glu), con- pression of Myc and its down-stream targets, as well as TMPRSS2-ERG stituting the first step of glutaminolysis. Glu is then transformed to α- fusion and Gleason score positively correlate with the pathway sig- ketoglutarate that enters to TCA producing citrate and malate for nature of PCa cells [15]. synthesis of fatty acids and nucleotides [56]. In solid tumors lacking In SOG pathway, THF is consumed during conversion of Ser to Gly. glucose, glutaminolysis is of inevitable importance. In PCa, mutations As discussed above, using THF antimetabolite MTX, Ser-to-Gly con- in mitochondrial DNA are frequent and result in impairment of TCA version can be inhibited. This phenomenon resulted in the in the dose- cycle and/or OXPHOS, forcing the cancer cells to use alternative dependent antiproliferative effects in metastatic PCa (PC-3) cells [15]. pathways [23]. This process can be mechanistically influenced by a Moreover, MTX-administered cells exhibited no changes in glycolysis number of oncogenes, including MYC, AR or mTOR that converge to and OXPHOS pathways; however, massive inhibition of purine synth- increase Gln uptake in PCa through elevating expression of distinct Gln esis and ATP/adenosine diphosphate concentration occurred due to Ser- transporters (SLC1A4, SLC1A5, etc.)[57]. These data highlight that to-Gly deregulation. oncogenic drivers have a pronounced impact on a promotion of Gln uptake and its metabolism, which underpins Gln importance for pro- 4.2. Glycolysis and mitochondrial metabolic pathways liferation of PCa cells. Indeed, in a recent study by Zacharias et al. it was described that highly aggressive, metastatic subline of PC-3 cells Pathways driving aerobic glycolysis and the biosynthesis of Ser and markedly increases Gln utilization [58], supporting the hypothesis that Gly are interconnected through the embryonic form of pyruvate kinase metastatic progression of PCa requires glutaminolysis. This phenom- (PKM2) that catalyzes the final step in glycolysis generating pyruvate enon makes enzymes of Gln metabolism highly promising, therapeutic and ATP. Single switch to PKM2 is necessary for the shift from OXPHOS targets. Unsurprisingly, several glutaminase small molecule inhibitors to glycolysis as was described for a variety of cancers, including PCa have been developed and some of them are currently being evaluated in [26,68]. The enhanced glycolysis can decrease reactive oxygen species clinical trials [59]. (ROS) and promote the pentose phosphate, and Ser/Gly synthesis To control Gln metabolic hierarchy, carbohydrate restriction diets pathway, which are both linked to tumorigenesis of PCa [45,62,63,69]. resulting in moderate ketosis have shown effect on stabilization of Ser can also act as an allosteric activator of PKM2. This phenomenon cancer remission [24]. Such deprivation can be enhanced via chemical results in accumulation of glycolytic metabolites under conditions of extracorporeal blood treatment arranging low glucose and Gln in dia- Ser deprivation and consequent channeling them into the Ser bio- lysate [60]. Such process should adversely damage tumor angiogenesis, synthesis [16,70]. Another enzyme crucial for the feeder reactions of and might be accompanied by application of conventional chemother- carbon from TCA to crucial biosynthetic processes is phosphoenolpyr- apeutics. We anticipate that this methodology merits further in- uvate carboxykinase isoform 2 (PCK2) that catalyzes the conversion of vestigation and could be helpful particularly for therapy of poor-prog- oxaloacetate to phosphoenolpyruvate (PEP) [71]. PCK2 is critical for nosis metastatic PCa exhibiting high glutaminolysis demands. metabolic switch and the maintenance of tumor-initiating cells (TICs) playing vital role in progression and metastasis of PCa. Zhao et al. re- 4. Ser (2-amino-3-hydroxypropanoic acid) vealed that TIC-enriched PCa cells utilize more glucose and secreted more lactate than TIC-low clones [72]. Inhibition of PKM2 activity Recent studies have highlighted the importance of Ser biosynthetic channeled more carbon through PEP to Ser synthesis for TICs, while the and metabolic pathway for PCa making this non-essential amino acid a elevation of PCK2 activity enriched TICs through reducing the TCA potential therapeutic target for its treatment [25,61]. Ser together with cycle, ROS level, and production of citrate and acetyl-coenzyme A. Gly are vital components in the anabolic building blocks for the gen- Moreover, reported datasets indicate that PCa patients exhibiting eration of glutathione, nucleotides, phospholipids, and other metabo- higher PCK2 expression develop more aggressive PCa phenotype with lites. An increased synthesis of Ser was found to be a marker of poor lower survival rates (Fig. 4). These data indicate that PCK2 is a po- prognosis of subjects suffering from PCa [15]. Up to this date, phos- tential target for novel therapies targeting TICs. phoglycerate dehydrogenase (PHGDH), the first enzyme of the de novo Ser synthesis pathway, was found to be amplified in distinct types of 4.3. Zinc metabolism and its linkage to metabolism of amino acids cancer [62,63]. Therefore, PHGDH is considered another druggable target for development of small molecule inhibitors as evidenced by Failure in intracellular zinc accumulation is a key hallmark in Pacold et al. [64]. prostate carcinogenesis. In our study, PNT1A, 22Rv1, and PC-3 cell lines, depicting different stages of PCa progression, and their zinc-re- 4.1. SOG pathway sistant counterparts were established and used to examine the impact of the intracellular increase in Zn(II) ions on distinct phenotypic para- Fraction of the synthesized Ser is utilized for production of ATP in a meters [19]. Interestingly, it was found that long-term zinc treatment pathway comprising de novo Ser synthesis, one carbon (folate) meta- re-routes cell metabolism from benign to more malignant phenotype. bolism and Gly cleavage system (termed SOG pathway). Ser provides PCa cell lines universally displayed high accumulation of aspartate one‑carbon units to THF to form 5,10-methylene-THF and, subse- (Asp) and Sar and depletion of essential amino acids. Noteworthy, in- quently, 5-methyl-THF that is an intermediate in the methylation of creased Asp/Threonine (Thr), Asp/Met, and Sar/Ser ratios were asso- homocysteine (Hcy) to methionine (Met), via Hcy methyltransferase ciated with malignant phenotype. This shed light onto the potential use (Met synthase). Schematic depiction of SOG pathway is shown in Fig. 3. of high-throughput analysis of intracellular amino acids patterns for Clinical studies with stable isotopic tracers suggest that virtually all diagnostic and prognostic purposes. of the methyl groups used for the total body remethylation of Hcy are Despite above mentioned, serum Ser level as well as the levels of derived from Ser [65]. This ensures sufficient Met pool for Met cycle, metabolites along the choline oxidation pathway were not found to be subsequent synthesis of major methyl-donor SAM [66], and also for the associated with PCa risk [73]. Nevertheless, it should be noted that formation of Gly, cysteine (Cys), taurine (Tau) and phospholipids [67]. individuals with a high Gly/Ser ratio were at a decreased risk of

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Fig. 3. Schematic illustration of SOG pathway. 5,10-CH2THF – 5,10-methylenetetrahydrofolate, 5-CH3THF – 5-methyltetrahydrofolate. Adapted and modified ac- cording to Davis et al. [65]. developing PCa. This phenomenon indicates that Gly/Ser metabolic collected from subjects with no evidence of malignancy [78]. Since PCa pathway deserves a detailed investigation that could provide inter- cells generally tend to accumulate Pro to scavenge ROS (discussed esting insights into the biology of PCa development. below), such contradiction could be explained by the minor role of Pro within the nutrient mixture (or marked synergistic effect of mixture components). 5. Proline (pro, pyrrolidine-2-carboxylic acid)

Pro is a non-essential imino acid with important roles in primary 5.1. Pro and apoptotic signaling metabolism of carbon and nitrogen, protection against osmotic and oxidative stress, protein chaperoning, cellular signaling, apoptosis and Pro catabolic pathway takes place in mitochondria, where Pro is adaptation to nutrients. Pro is also necessary for protein synthesis and oxidized to Glu through P5C (pyrroline-5-carboxylate) in a two-step structure, biosynthesis of amino acids and polyamines, wound healing, enzymatic reaction catalyzed by proline dehydrogenase/proline oxi- ROS scavenging, and immune response [74,75]. It has been described dase (PRODH/POX) and P5C dehydrogenase (P5CDH). Conversely to that nutrient formulations comprising Pro exhibit inhibitory activity in this reaction, P5C synthetase (P5CS) and P5C reductase (PYCR) convert distinct PCa cells and xenograft models [76,77]. On the other hand, we Glu into Pro. This pathway has been shown to be double-edged sword have identified elevated urinary Pro levels in patients with diagnosed acting either as PCa suppressor by initiating ROS-mediated apoptosis, PCa, whereas virtually no Pro was identified in urinary specimens or as tumor survival factor through ATP production or ROS-induced

Fig. 4. PCa datasets indicating a role of PCK2 expression for a development of more aggressive PCa phenotype with lower survival rates. Adapted and modified from Zhao et al. [72].

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6.1. Inhibition of Arg metabolism as therapeutic target

It is known that stimulated metabolism of Arg within PCa tissue may contribute to the growth, angiogenesis, metastasis, and tumor-related immunosuppression [88,89]. Levels of the inducible form of NOS (iNOS) and arginase are therefore frequently up-regulated in prostate tumors compared to hyperplastic prostate [29,90]. Therefore, it is not surprising that strong iNOS expression was found to be a predictor for poor survival of PCa patients [91]. Treatment of PCa cultures with in- hibitors of NOS or arginase resulted in activation of CD8 lymphocytes, prolonged their survival and restored their lytic capacity suggesting the role of Arg metabolism in tumor-associated immunosuppression [29].

6.2. Arg deprivation

Arg deprivation has been studied as a potential anticancer therapy, however with a limited success. Despite that, recent development of PEGylated arginine deiminase (ADI-PEG 20) enlarged possibilities of Arg deprivation in tumors [30]. PCa tissues have been shown to fre- Fig. 5. Differential functions of POX under hypoxia and low glucose conditions. quently lack expression of argininosuccinate synthetase (ASS), a ubi- Hypoxia, low glucose, and combined low glucose and hypoxia upregulated POX quitous enzyme involved in the two-step synthesis of Arg from citrulline through the same mechanism: the AMPK pathway. Under low glucose condi- [92]. Unable to synthesize their own Arg, ASS-deficient cells depend on tion, POX is used preferentially for ATP production, while under hypoxia with relatively inefficient amino acid transporters [93]. Arg deaminase (ADI) adequate glucose POX mediated ROS production. Adapted and modified from isolated from Mycoplasma degrades Arg into citrulline. In native form, Liu et al. [27]. ADI is unstable and highly antigenic. PEGylation (in ADI-PEG 20 for- mulation) increases ADI stability and decreases its immunogenicity autophagy (Fig. 5 [79–81]). allowing to be used for decreasing of plasmatic Arg to undetectable Pro biosynthesis was also identified as crucial for maintaining pyr- levels. Due to the lack of ASS, ADI-PEG 20 induces a late caspase-in- idine nucleotide levels by connecting the Pro cycle to glycolysis and dependent cell death in CWR22Rv1, but not LNCaP in vitro [94]. pentose phosphate pathway [82], and therefore might provide a pro- Noteworthy, in 2018, ADI-PEG 20 completed Phase III clinical trial mising target for PCa therapy. for hepatocellular carcinoma, exhibiting a significant prolongation of overall survival in patients with successful depletion of Arg [30]. Hopefully, further tests of Arg deprivation for PCa management will be 5.2. Pro and ROS scavenging conducted to extend the therapeutic possibilities.

Pro acts as efficient ROS scavenger and was found to inhibit apop- 7. Leucine (Leu, 2-amino-4-methylpentanoic acid) tosis induced by oxidative agents [83]. In metastatic PCa (PC-3) cells three-times higher content of Pro was found in comparison to normal Leu is an essential amino acid known to be important for protein prostatic cells, corresponding to the intrinsic chemoresistance of PC-3 synthesis [95]. Leu activates the mTOR signaling pathway that controls cells to those agents [28]. Interestingly, pre-incubation with Pro in- mRNA translation, ribosome biogenesis, autophagy, and cell metabo- creased the tolerance of normal cells to H O . Protective activity of Pro 2 2 lism. In PCa deregulation of mTOR contributes to tumor progression against ROS can be inhibited by knocking-down PRODH. This process and stimulation of a castration resistance [31]. Leu is internalized by leads to attenuated phosphorylated levels of Akt and FoxO3a and de- proteins belonging to a complex L-type amino acid transporters (LATs) creased cell survival. These data highlight the importance of Pro cata- family. Interestingly, LAT1 and LAT3 have been found up-regulated bolism not only for producing the building blocks crucial for rapidly during distinct stages of PCa pathogenesis. In PCa xenografts, knock- proliferating PCa cells, but also for their susceptibility to the environ- down of LATs inhibits cell cycle progression and tumor growth and led mental stressors (chemo-, radio-therapy). In recent years, several to a spontaneous regression of metastasis [32]. Metastatic (LNCaP and competitive PRODH inhibitors have been developed (L-tetra- PC-3) cells administered with Leu analogue 2-aminobicyclo-(2,2,1)- hydrofuroic acid, 5-oxo-2-tetrahydrofurancarboxylic acid or N-pro- heptane-2-carboxylic acid (BCH) that allosterically blocks LATs exhibit pargylglycine) [84,85]. Nevertheless, further investigation might be a significant decrease in cell growth and viability and display arrests of done to develop novel more effective and less toxic PCa therapeutics. cell cycle in G0-G1 phase. Moreover, microarray screening revealed that BCH down-regulates cell-cycle-check-point genes UBE2C, CDC20 and 6. Arginine (Arg, 2-amino-5-guanidinopentanoic acid) CDK1 and up-regulates ID1,3,4 transcription factors inhibiting their transcription activation. It is worth to note, that the BCH-down-regu- Arg is a semi-essential amino acid synthesized from Gln, Glu and Pro lated genes found in PCa cell lines have also been found to be up- via the intestinal-renal axis. Arg degradation occurs via multiple path- regulated in metastatic PCa specimens [32,95]. These findings indicate ways that are initiated by arginase, Arg:Gly amidinotransferase, and that targeting of LAT1/3 could be a promising way for developing Arg decarboxylase. These pathways produce nitric oxide, polyamines, modalities for precise therapy of metastatic, castration resistant PCa via Pro, Glu, creatine, and agmatine with each having enormous biological suppression of mTOR activity and M-phase cell cycle genes. Indeed, a importance. Arg is a nutritionally essential amino acid vital for sper- wide spectrum of LAT family inhibitors has been developed and suc- matogenesis, embryonic survival, foetal and neonatal growth, as well as cessfully tested in pre-clinical models (structures of selected LAT in- maintenance of vascular tone and hemodynamic [86]. Arg can be also hibitors are depicted in Fig. 6)[42]. However, since the LATs shares the metabolized by the nitric oxide synthase (NOS), to generate the free majority of substrates, these inhibitors target all members of LAT fa- radical nitric oxide (NO) and citrulline. In the prostate tissue NO has a mily, which is highly undesirable for clinical translation. Therefore, crucial physiological role for smooth muscle tone and proper secretory intensive efforts might be made to develop inhibitors precisely tar- functions [87]. geting LAT1 and LAT3.

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mitogenic factor involved in cancer growth and angiogenesis, cell mi- gration, and metastasis [98]. Serotonin-producing neuroendocrine cells are found in normal prostate tissue, as well as in PCa specimens. These cells are more commonly encountered in high-stage and high-grade PCa, with the highest concentrations occurring in castration-resistant PCa [36]. It is known that as a consequence of Trp shortage, T-lymphocytes undergo proliferation arrest [37]. Therefore, a degradation of Trp by indoleamine 2,3-dioxygenase (IDO) produced by multiple human tu- mors including PCa has been proposed as a mechanism favoring tumor escape from immune response [99]. Since PCa demonstrates high levels of IDO compared to benign hyperplasia, correlating with serum ky- nuerine/Trp ratio [100], this molecular mechanism might be utilized for enhancing options for PCa diagnostics.

10. Sarcosine (Sar, (2-methylamino)acetic acid)

Sar (also N-methylglycine) is an intermediate in Gly synthesis and degradation pathway. In 2009 Sar was delineated as a differential metabolite indicating presence of PCa. Furthermore, Sar level in pros- tate tissue, plasma and urine was found to be highly increased during Fig. 6. Structures of Leu and selected LAT inhibitors. PCa progression to metastasis. Intracellular Sar levels were also in- creased in invasive PCa-derived cell lines relative to benign prostate epithelial cells [38]. Due to its presence in urine it was proposed as 8. Methionine (Met, 2-amino-4-(methylthio)butanoic acid) putative non-invasive PCa marker, but later this conclusion has been disputed [101]. Met is an essential amino acid that is necessary for growth, devel- From other published studies, it follows that Sar and its metabolism opment, and homeostasis of mammalian cells. Met is synthesized en- are undoubtedly connected with PCa pathogenesis. Multiple amino dogenously either by homocysteine (Hcy) methylation in the presence acids mentioned in this review are involved in Sar metabolism, espe- of betaine co-factor and 5-methyl-THF or, putatively, through the cially Gly, Cys, Met, Ser, Glu, Hcy and Tau. Scheme in Fig. 7 shows that polyamine biosynthesis pathway [96]. Catabolic product of Met is Sar, Sar metabolism is interconnected with biosynthesis of nucleotides, widely-discussed, non-invasive PCa biomarker and oncometabolite, control of redox environment, lipid metabolism, control of translation whose importance for PCa is discussed below [38]. and DNA methylation [17]. Together with Cys, Met is one of the two sulfur-containing protei- nogenic amino acids, and its metabolites serve as major methyl donors. 10.1. Sar metabolism – small but mighty Accordingly, Met is involved in several biochemical pathways that provide molecular compounds for protein synthesis, chromatin and Sar metabolism comprises four parts – Sar pathway, folate cycle, protein methylation, and synthesis of glutathione. In androgen-in- Met cycle and transsulfuration pathway. Sar pathway has been found to sensitive PCa cell lines, Met restriction stops proliferation and induces be regulated by androgen receptor and ERG gene fusion product [38]. apoptosis [33]. The major enzymes regulating metabolism of Sar are glycine N- Met metabolites provide superior sensitivity and specificity in methyltransferase (GNMT), sarcosine dehydrogenase (SARDH), and L- multivariable prediction models for rapid biochemical recurrence fol- pipecolic acid oxidase (PIPOX). In cells, Sar is generated by the enzy- lowing prostatectomy. Amounts of urinary products of Met catabolism matic transfer of a methyl group from SAM to Gly with the concomitant correlate with PCa progression status [34]. Hence, the quantitation of production of S-adenosylhomocysteine (SAH). This reaction is cata- Met metabolites as biomarkers would significantly increase the ability lyzed by GNMT that is expressed at high levels in mammalian liver, to predict aggressive PCa features and risk of early biochemical recur- exocrine pancreas and prostate [102]. The Sar-metabolizing enzymes, rence over existent clinical variables including serum PSA, biopsy and SARDH and PIPOX, catalyze the oxidative demethylation of Sar con- Gleason score. verting it back to Gly (Fig. 7)[103]. Alterations in Met metabolism and Met dependency have been de- It was found that up-regulation of the polycomb group protein EZH2 scribed in numerous cancer cell lines. Unlike normal cells, tumor cells that drives progression of PCa also stimulates production of Sar [104]. are mostly not able to utilize Hcy as Met precursor. Met restriction Interestingly, EZH2 knock-down in metastatic PCa cells (DU-145) leads blocks the cell cycle and induces apoptosis in metastatic (PC-3 and DU- to decrease in Sar and consequent inhibition of PCa invasiveness. Fur- 145) PCa cells [33,35]. Poirson-Bichat and coworkers have demon- ther, it was shown that Sar induces invasion of benign RWPE prostate strated that proliferation rate of PC-3 cells is greatly reduced in Met-free cells [38]. Interestingly, knock-down of SARDH results in an increase in medium, while proliferation rate of DU-145 cells is affected only endogenous Sar together with a marked increase in invasiveness [38]. slightly [97]. Addition of Hcy mildly increases the proliferation rate of Khan et al. extended this study and shown that knock-down of SARDH PC-3 cells, while proliferation of DU-145 cells can be fully recovered. In also pronouncedly stimulates cellular proliferation and anchorage-in- PC-3 murine xenografts fed by Met-free Hcy-rich diet together with dependent growth [105], indicating plausible role of Sar in metastatic injection of Met analogue ethionine, slower growth of the tumor was potential of PCa. Interestingly, when knocking-down another Sar N- observed suggesting usability of Met deprivation diet in castration re- demethylating enzyme PIPOX, the same cells increased invasiveness, sistant PCa. but without effect on proliferation and anchorage-independent growth. Attenuation of GNMT in DU-145 PCa cells results in a significant 9. Tryptophan (Trp, 2-amino-3-(1H-indol-3-yl)propanoic acid) reduction in cell invasion, with a concomitant threefold decrease in the intracellular Sar compared to control (mock) cells. Interestingly, addi- Trp is an essential amino acid used for protein synthesis and as the tion of exogenous Sar does not completely rescue invasive phenotype of precursor molecule for biosynthesis of serotonin. Serotonin may act as these [105], most likely due to fast degradation rates of SARDH and

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Fig. 7. Scheme of metabolical pathway of Sar biosynthesis and degradation to its non-methylated precursor Gly and its connection to other important metabolical pathways. Enzymes in scheme are numbered and depicted as follows: 1, DMGDH, dimethylglycine dehydrogenase; 2, GNMT, glycine-N-methyltransferase; 3, SARDH, sarcosine dehydrogenase; 4, SHMT1/2, serine hydroxymethyltransferase; 5, MTHFR, 5,10-methylenetetrahydrofolate reductase; 6, MTR, methionine synthase; 7, BHMT, betaine-homocysteine methyltransferase; 8, CHDH, choline oxidase; 9, MAT, methionine adenosyltransferase; 10, SAM-dependent methyltransferase; 11, PEMT, phosphatidylethanolamine methyltransferase; 12, AHCY, S-adenosylhomocysteine hydrolase; 13, CBS, cystathionine β-synthase; 14, CTH, cystathionase; 15, GCL, glutamate-cysteine ligase; 16, GSS, glutathione synthetase; 17, CDO1, cysteine dioxygenase 1; 18, CSAD, cysteine sulphinic acid decarboxylase; 19, GOT1, glutamate oxaloacetate transaminase 1. Dmg – dimethylglycine, SAM – S-adenosyl-methionine, SAH – S-adenosyl-homocysteine, PE – phosphatidylethanolamine, PC – phosphatidylcholine, and THF – tetrahydrofolate. Adapted and modified from Heger et al. [17].

PIPOX. exposed tumors accumulated Gly, Ser and Sar, and exhibited high ex- As shown in our pilot study, amino acids closely related to Sar pression of SARDH indicating the necessity for Sar metabolic de- metabolism, can significantly affect the expression of GNMT-encoding gradation. High-throughput cDNA microarray revealed that Sar affects mRNA in prostate cells as well as their growth attributes [17]. These the expression of genes driving apoptosis, proliferation and cell cycle, results indicate that Sar production is triggered by dimethylglycine indicating a direct effect on the growth of PCa. (Dmg) administration more than by Gly. However, Gly, a well-known In urine of PCa patients, Gly content negatively correlates with cancer-related metabolite, significantly influences the prostate cells amount of Sar [78]. This suggests the need of PCa for utilizing Gly for amino acid patterns, shedding interesting light onto a use of distinct Sar biosynthesis. Interestingly, in accordance with this fact, levels of Sar combinations of amino acids in deprivation therapy. are decreased in elderly patients who have a higher probability to suffer from non-aggressive PCa with a lower ability to produce Sar due to dysregulation of the enzymes producing and catabolizing Sar [106]. 10.2. Influence of Sar supplementation on prostate cells These data indicate that intracellular Sar pool is a crucial oncometa- bolite affecting PCa development and progression to more aggressive Exogenous supplementation of cells with physiologically relevant phenotypes. Nevertheless, the molecular mechanism responsible for amounts of Sar and its pathway-related amino acids triggers up- (par- this phenomenon is not known. Further studies might be carried out to ticularly in the case of Dmg) or down-regulation (due to administration shed light onto the possible use of Sar for PCa diagnosis and stratifi- with Gly, Sar and Dmg) of GNMT [17]. This indicates that prostate cells cation. Obvious importance of Sar metabolism for PCa aggressiveness can perform rapid reprogramming in a reaction to exogenous metabo- may lead to investigation of specific inhibitors capable to inhibit bio- lites affecting Sar metabolic pathway. synthesis of Sar. This might result in better efficiency in therapy of To deepen this knowledge, we analyzed Sar effect on murine PCa highly aggressive PCa. xenografts [39]. It was found that Sar stimulates a tumor growth and reduces weight of treated mice. Interestingly, we found that Sar-

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11. Hydroxyproline (Hyp, 2S,4R)-4-hydroxypyrrolidine-2- and combined with standard chemotherapy. These approaches defi- carboxylic acid nitely merit further detailed investigation. Finally, it should be noted that PCa is a highly heterogeneous dis- Hyp is post-translational metabolite of Pro, vital for maintaining cell ease with distinct metabolic alteration fingerprints. Therefore, only a structure and function [107]. The unique ring structure of Pro and Hyp detailed knowledge about these signatures can result in subsequent distinguishes them from other amino acids in terms of rigidity, chemical application of a proper therapeutic modality towards the new oncologic stability, and biochemical reactions [108]. Hyp is recognized as a paradigm of precision medicine. substrate for the synthesis of Gly, pyruvate, and glucose, and also may scavenge oxidants and regulate the redox state of cells [40]. Acknowledgements In past, total urinary Hyp has been shown to be more reliable than other markers indicating the presence and activity of PCa bone me- This work was financially supported by the Czech Science tastases [109] that are a major cause of PCa morbidity. Hyp is released Foundation (GA CR 16-18917S). The authors also gratefully acknowl- into the circulation once PCa invades bone and is metabolized by the edge CEITEC 2020 (LQ1601). liver or excreted in the urine. Importantly, in PCa bone metastases, not only osteoid formations adjacent to tumor tissue, but also bone re- Conflict of interest sorption is frequently accelerated. It is worth to note that the accel- eration of bone resorption can be evidenced by the increase in urinary Authors declare none. Hyp excretion, bone histomorphometry and the presence of lytic bones on radiographs. Based on these data, attempts have been made to use References the urinary Hyp index (Hyp/mg creatinine) as biomarker of metastatic PCa [41]. 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